Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450

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Early downregulation of Mcl-1 regulates apoptosis triggered by cardiac glycoside UNBS1450

Published Article
Cell Death and Disease
Nature Publishing Group
Publication Date
DOI: 10.1038/cddis.2015.134


Cardiac glycosides (CGs), prescribed to treat cardiovascular alterations, display potent anti-cancer activities. Despite their well-established target, the sodium/potassium (Na + /K +)-ATPase, downstream mechanisms remain poorly elucidated. UNBS1450 is a hemi-synthetic cardenolide derived from 2″-oxovorusharin extracted from the plant Calotropis procera, which is effective against various cancer cell types with an excellent differential toxicity. By comparing adherent and non-adherent cancer cell types, we validated Mcl-1 as a general and early target of UNBS1450. A panel of CGs including cardenolides ouabain, digitoxin and digoxin as well as bufadienolides cinobufagin and proscillaridin A allowed us to generalize our findings. Our results show that Mcl-1, but not Bcl-xL nor Bcl-2, is rapidly downregulated prior to induction of apoptosis. From a mechanistic point of view, we exclude an effect on transcription and demonstrate involvement of a pathway affecting protein stability and requiring the proteasome in the early CG-induced Mcl-1 downregulation, without the involvement of caspases or the BH3-only protein NOXA. Strategies aiming at preventing UNBS1450-induced Mcl-1 downregulation by overexpression of a mutated, non-ubiquitinable form of the protein or the use of the proteasome inhibitor MG132 inhibited the compound's ability to induce apoptosis. Altogether our results point at Mcl-1 as a ubiquitous factor, downregulated by CGs, whose modulation is essential to achieve cell death. Cardiac glycosides (CGs) possess well-established pharmacological properties, which were more recently reconsidered for novel clinical uses. Originally prescribed to treat cardiovascular alterations, CGs also display interesting anti-cancer activities. Epidemiological studies correlated a reduced incidence of specific cancer types with the regular intake of selected CGs. 1,2 Preclinical in vitro and in vivo research demonstrated the ability of CGs to impact cell proliferation and survival of a variety of cancer cell models 3 at low nanomolar concentrations. Of interest, CGs also affect cancer cell models typically resistant to canonical cytocidal agents. 4–6 Furthermore, combinational treatments triggered synergistic effects. 7–9 Besides apoptosis, CGs were also able to induce autopha-gic cell death, anoikis or immunogenic cell death. 10–12 This heterogeneity reflects the extraordinary cytocidal potential of these compounds and reveals cross-talks existing among different cell death modalities as described for other natural compound acting as anti-cancer agents. 13 CGs possess a steroid core structure and are subdivided in two families depending on the chemical group on the D-ring at position 17: cardenolides (UNBS1450, ouabain, digitoxin and digoxin) contain a butyrolactone group, whereas bufadieno-lides (cinobufagin and proscillaridin A) exhibit an α-pyrone group. A sugar moiety on the A-ring of the steroid nucleus at position 3 determines pharmacokinetic and pharmacodynamic properties. Sugar moiety and lactone are in cis-conformation. 14

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